The performance of available small animal PET scanners continues to be detector rather than physics limited. Significant improvements in the sensitivity and spatial resolution of a small animal PET scanner would not only improve the quantification of signals that we are currently able to visualize (by reducing partial volume effects and increasing signal-to-noise) but would also open up important new applications that are beyond the reach of contemporary animal PET systems. The goal of the original application was to develop depth-encoding PET detectors that simultaneously exhibit high spatial resolution and high efficiency by using dual-ended readout of high-efficiency and finely pixelated scintillator arrays with position sensitive avalanche photodiodes (PSAPDs). During the fourth year of the current grant, we have successfully developed both rectangular and tapered lutetium oxyorthosilicate (LSO) arrays with crystal sizes down to 0.5 mm, very high efficiency (20 mm thick detectors) and a depth of interaction (DOI) resolution of ~ 2 mm. A prototype PET scanner was developed using these depth encoding detectors and it was shown that detector efficiency, spatial resolution and spatial resolution uniformity can be greatly improved by using our new detectors compared with the detectors used in commercial small-animal PET systems. The aims of this renewal are to apply this detector technology and develop a high spatial resolution (~0.5 mm) and high sensitivity (~20%) preclinical PET scanner designed for molecular imaging studies in the mouse brain. The proposed research plan will also involve developing novel data correction and image reconstruction algorithms to fully utilize the high spatial and DOI capabilities of these detectors and to apply the scanner for selected proof-of-concept mouse brain imaging studies. The goals of this proposal are 1) to develop electronics and data acquisition for the proposed scanner; 2) to develop depth encoding detectors with even smaller crystal size; 3) to measure the contributions of positron range and photon acolinearity to the spatial resolution of a PET scanner; 4) to simulate whether gantry rotation and continuous bed motion will improve the image quality of the proposed scanner; 5) to construct the proposed PET scanner; 6) to develop reconstruction and correction algorithms for the scanner; 7) to evaluate the performance of the scanner; 8) to perform selected in-vivo mouse brain imaging studies. The overall impact of this proposal is that it will lead to a preclinical PET scanner based on novel depth- encoding solid state detectors and tapered scintillator arrays that provides an unprecedented combination of spatial resolution and sensitivity for molecular imaging of the mouse brain. This will open up new opportunities for quantitative molecular imaging studies of development and aging, studies of murine disease models (Alzheimer's disease, Parkinson's disease, stroke, and neurodevelopmental disorders to name but a few), and monitoring of novel therapeutic strategies based on small molecules, peptides, nanoparticles, gene therapies or cellular therapies.